By: Shalmali Pal
From: medpagetoday.com
“Medical Journeys” is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. “Medical Journeys” chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
The first-line, standard of care for patients with HR-positive/HER2-negative breast cancer is a combination of endocrine therapy (ET) with cyclin-dependent kinase (CDK)4/6 inhibitors. This dual-therapy approach targets a pathway that promotes cell division and inhibits it.
CDK4/6 inhibitors can also be combined with fulvestrant (Faslodex) as was done in clinical trials that paired the agent with palbociclib (Ibrance; PALOMA‑3
), ribociclib (Kisqali; MONALEESA‑3), and abemaciclib (Verzenio; MONARCH‑2
). PALOMA-3 led to progression-free survival (PFS) improvements while MONALEESA-3 and MONARCH-2 boosted overall survival (OS).
Endocrine resistance continues to be a persistent challenge, as summarized in a previous article
in this Medical Journeys series. Novel and emerging therapies to counter this resistance, and/or to treat patients whose cancer progresses during first-line treatment, have made great strides over the past decade.
of a specific inhibitor or inhibitors may allow re-tooling
of this class of therapy to treat patients whose disease progressed on prior CDK4/6 inhibitors and ET.
Switching ER, with or without changing a CDK4/6 inhibitor, improved PFS in the MAINTAIN
trial; add-on abemaciclib upgraded PFS after disease progression in the postMONARCH
trial.
Selective estrogen receptor degraders (SERDs) are a class of drugs typically used as second-line therapy
if the cancer has progressed after first-line CDK4/6 inhibitor treatment. They can be used alone or in combination with other drugs.
Examples with FDA approval in various lines of treatment are intramuscular injectable fulvestrant
; oral elacestrant (Orserdu); and imlunestrant
(Inluriyo).
On-trial oral SERDs include camizestrant
and giredestrant.
Trials such as SERENA-6
are testing circulating tumor DNA (ctDNA) to guide treatment changes ahead of disease progression in patients with advanced breast cancer.
A proteolysis-targeting chimera (PROTAC) protein degrader is a bifunctional molecule
that uses the body’s protein-degradation system to eliminate specific targeted proteins. The approach does not just inhibit, but actually destroys, harmful proteins.
PROTACs at various stages of investigation include vepdegestrant versus fulvestrant (VERITAC-2
trial); vepdegestrant plus palbociclib; and oral AC699 and HP568.
Antibody-drug conjugates (ADCs) represent a major advance in the HR-positive/HER-negative breast cancer treatment landscape, and are increasingly replacing standard chemotherapy in later-line settings for metastatic disease. Similarly, inhibitors of the PI3K/AKT/mTOR pathway — a commonly mutated signaling pathway in HR-positive breast cancer that can drive resistance to ET and CDK4/6 inhibitors — and PARP inhibitors, which target cancer cells with homologous recombination repair deficiencies, which are usually caused by inherited BRCA1/2 mutations, have both made tremendous inroads.
ADCs deliver chemotherapy directly to cancer cells while minimizing damage to healthy tissue. Examples include:
- Datopotamab deruxtecan (Dato-DXd; Datroway) targets and delivers chemotherapy to cells expressing the trophoblast cell-surface antigen 2 (TROP2) protein. TROPION-Breast01 demonstrated a PFS improvement with Dato-DXd.
- TROP2-directed sacituzumab govitecan (SG; Trodelvy) led to better OS in TROPiCS-02.
- Trastuzumab deruxtecan (T-DXd; Enhertu), is a HER2-targeting ADC that is used in ET-treated HER2-low or HER2-ultralow disease and offered meaningful results in DESTINY-Breast04. In a 2025 real-world data analysis of T-Dxd versus SG, the former offered better relative outcomes.
PI3K/AKT/mTOR is one of the most frequently activated pathways in HR-positive breast cancer. It can be caused by activating mutations in the PIK3CA gene; loss of the tumor suppressor phosphate and tensin homolog (PTEN) gene, which typically inhibits the pathway; or upregulation of receptor tyrosine kinases such as IGF-1R, which are upstream of PI3K. The activation of this pathway promotes cell growth and survival, leading to resistance from endocrine therapy.
Approved agents include:
- Inavolisib (Itovebi) as part of triplet therapy (Itovebi) showed a significant OS benefit in INAVO120.
- Alpelisib (Piqray) plus fulvestrant prolonged PFS in the SOLAR-1 trial, while BYLieve confirmed the PFS benefit of the same dual-agent treatment in patients pre-treated with CDK4/6 inhibitors.
- AKT enzyme-targeting and -blocking capivasertib (Truqap) is used with fulvestrant to treat pre-ET-treated patients with ≥1 alterations in the PIK3CA, AKT1, or PTEN genes. CAPItello-291 showed a better median PFS with the combination.
- The mTORC1 inhibitor everolimus combined with the steroidal aromatase inhibitor (AI) exemestane (Aromasin) is standard treatment for HR-positive/HER2-negative metastatic breast cancer with resistance to prior non-steroidal AI therapy, per BOLERO-2. Everolimus plus fulvestrant can extend PFS in postmenopausal women with HR-positive, HER2-negative, AI-resistant disease.
PARPs are nuclear enzymes
that catalyze the transfer of ADP ribose from nicotinamide adenine dinucleotide (NAD+) to target proteins and facilitate DNA repair. Inhibition of PARP1 by RNA interference with chemical inhibitors leads to severe, highly selective toxicity in BRCA1/2-deficient cells
(Lynparza) and talazoparib (Talzenna) are approved for metastatic disease with a germline BRCA mutation in patients who have already been treated with prior ET, or are ineligible for ET, based on results from OlympiAD and EMBRACA
. Improved PFS was observed in both studies.
Immunotherapy (IO) combinations — such as CDK4/6 inhibitors with immune checkpoint inhibitors (PD-1/PD-L1 inhibitors, for instance) or IO with chemotherapy — is a relatively recent treatment option. The results of investigations have been modest in terms of benefit, largely because HR-positive tumors are immunologically cold.
Although there is currently not enough evidence for routine IO use
in HR-positive/HER2-negative breast cancer, more research is ongoing.
Continuing advances in precision medicine and biomarker-driven strategies will enable more personalized treatment approaches that improve outcomes and delay disease progression
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.